SUMMARY ? CORE C: MELANOMA SCREENING AND STRATIFICATION The focus of this P01 is the biological interplay between metabolism, endoplasmic reticulum (ER) stress, and mitochondrial biogenesis and function in melanoma. Alterations in these functions may promote therapeutic resistance and at the same time create novel drug sensitivities. Thus, a goal of the P01 will be to understand the mechanisms underlying deregulation of central metabolism, ER stress pathways, and mitochondrial biogenesis and function, and their significance for melanoma development and response to therapy. These studies will provide the basis for melanoma stratification based on changes in pathway activities, independent of the BRAF and NRAS genotypes. The extensive collaboration among all programs and cores using well- annotated melanoma cultures and tissues is essential for success of the P01. Core C will play a critical role in association with Projects 1, 2, and 3 and Core B to achieve the goals of the P01. First, we will provide biomaterials (melanoma cell cultures and tissue) for experimental use by each of the projects. Second, the core will also carry out single-agent and combination high-throughput screening for sensitivity of melanoma to select therapeutic agent libraries developed by the core. Third, we will integrate drug sensitivity data with genetic, transcriptomic, and proteomic data on the cell cultures and tissues to be analyzed. Finally, we will provide comprehensive pathology support and access to clinically annotated archival human melanoma tissue for translational studies.